StreptoMANIAC · Cost and benefit of beta-lactam resistance in Streptococcus pneumoniae: interplay between the resistance determinants and the cell elongation/division components
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2019-11-01 → 2021-11-30
- EU contribution
- €183,473
- Participants
- 1
- Scheme
- MSCA-IF-EF-CAR
Lines connect the coordinator with its partners.
Results in brief
Cost and benefit of beta-lactam resistance in Streptococcus pneumoniae: interplay between the resistance determinants and the cell elongation/division components
Streptococcus pneumoniae (the pneumococcus) is one of the most important human pathogens that can cause a broad spectrum of diseases such as otitis media, pneumonia, bacteraemia and meningitis. Pneumococcal diseases lead to over a million deaths per year and especially the individuals with a compromised immune system are affected. Beta-lactam antibiotics, such as penicillin, have been successfully used for many decades to treat pneumococcal infections. However, penicillin-resistant S. pneumoniae strains, which are often resistant also to other classes of antibiotics, have increased dramatically since the 1980s and pose serious problems in the treatment of infections. This led the World Health Organization in 2017 to include S. pneumoniae on a list of priority pathogens for which research, discovery and development of new antibiotics is urgently needed. Despite the availability of antibiotic therapy and highly effective pneumococcal conjugate vaccines, which cover a minority of the 100 known pneumococcal serotypes, S. pneumoniae remains a critical clinical problem. Beta-lactam resistance in S. pneumoniae involves the modification of target enzymes for this class of antibiotics, the penicillin binding proteins (PBPs) as well as non-PBP components. In clinical isolates, three PBPs, namely PBP2x, PBP2b and PBP1a, are the main players in the development of beta-lactam resistance and display a so called "mosaic" structure, which is the result of interspecies gene transfer followed by recombination events. These altered PBPs have reduced affinity for beta-lactams while the enzyme function remains unaffected, giving a selective advantage for the resistant strains to grow in the presence of beta-lactams. In some penicillin-resistant S. pneumoniae clones, non-PBP determinants are also involved and contribute to the resistance phenotype. The main objectives of the StreptoMANIAC project were to study the interplay between the different beta-lactam resistance determinants, thereby focusing on the molecular mechanisms and on the physiological and biochemical consequences of acquired resistance in S. pneumoniae clinical isolates.
Data: CORDIS, © European Union
Project objective
The widespread emergence of acquired resistance to antibiotics constitutes a serious threat to global public health. Among Gram-positive pathogens, Streptococcus pneumoniae (the pneumococcus) is a normal resident of the oral and nasal cavities but is also cause of otitis media and sinusitis as well as pneumonia, bacteremia and meningitis, particularly in young children and the elderly. Despite the availability of effective vaccines, S. pneumoniae remains an important clinical problem, also because of the increase of multi-drug resistant clinical isolates. S. pneumoniae is, indeed, listed by the WHO as one of the priority pathogens to drive research, discovery and development of new antibiotics. In S. pneumoniae, resistance to beta-lactam antibiotics represents a highly complex scenario, involving both target enzymes, the penicillin-binding proteins (PBPs), and non-PBP components, as the two-component system CiaRH. In clinical isolates, beta-lactam resistance is primarily mediated by the acquisition of multiple mutations in the transpeptidase domain of three of its six PBPs: PBP2x, PBP2b and PBP1a. These modified PBPs have reduced affinity for beta-lactams while leaving the enzyme function unaffected, thus conferring an advantage for the mutated strains in the presence of the antibiotics. However, PBPs are not only the beta-lactam target but are also essential enzymes involved the last stages of peptidoglycan biosynthesis, where they play specific roles in peripheral (side-wall) growth and cell division. Whereas the majority of studies so far concentrated solely on the effect of altered PBPs on resistance, little is known about the impact of the altered PBPs on PG biosynthesis, cell growth and division. Using a combination of genetic, biochemical, cytological and comparative genomics techniques, this study aims to fill in the knowledge gaps in the cost and benefit of acquired beta-lactam resistance in S. pneumoniae and in the complex mechanisms that regulate it.
Original text from CORDIS.
Participants
- UNIVERSITA DEGLI STUDI DI TRENTO · TrentoCoordinatorItaly
Links
Data: CORDIS, © European Union